Endothelial progenitor cells as therapeutic vectors in cardiovascular disorders: From experimental models to human trials

Ben-Shoshan, Jeremy; George, Jacob

doi:10.1016/j.pharmthera.2007.03.012

Cited by 44 publications

(49 citation statements)

References 108 publications

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“…This result suggests an improvement in vessel maturation and arteriogenesis, a mechanism known to be favored by ECFCs. 50,51 Our observations are consistent with the protective effects of RSV on the vascular system. [45][46][47][48] Together with RSV, small-molecule activators of SIRT1 have been proposed in the treatment of type 2 diabetes, 52,53 another disease associated with PT.…”

Section: Discussionsupporting

confidence: 87%

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Vassallo

Simoncini

Ligi

et al. 2014

Blood

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Key Points• We demonstrate that PT promotes ECFCs dysfunction by inducing stress-induced premature senescence.• Our data reveal that SIRT1 deficiency drives PT-ECFC senescence, and acts as a critical determinant of the PT-ECFC angiogenic defect.Epidemiological and experimental studies indicate that early vascular dysfunction occurs in low-birth-weight subjects, especially preterm (PT) infants. We recently reported impaired angiogenic activity of endothelial colony-forming cells (ECFCs) in this condition. We hypothesized that ECFC dysfunction in PT might result from premature senescence and investigated the underlying mechanisms. Compared with ECFCs from term neonates (n 5 18), ECFCs isolated from PT (n 5 29) display an accelerated senescence sustained by growth arrest and increased senescence-associated b-galactosidase activity. Increased p16INK4a expression, in the absence of telomere shortening, indicates that premature PT-ECFC aging results from stress-induced senescence. SIRT1 level, a nicotinamide adenine dinucleotidedependent deacetylase with anti-aging activities, is dramatically decreased in PT-ECFCs and correlated with gestational age. SIRT1 deficiency is subsequent to epigenetic silencing of its promoter. Transient SIRT1 overexpression or chemical induction by resveratrol treatment reverses senescence phenotype, and rescues in vitro PT-ECFC angiogenic defect in a SIRT1-dependent manner. SIRT1 overexpression also restores PT-ECFC capacity for neovessel formation in vivo. We thus demonstrate that decreased expression of SIRT1 drives accelerated senescence of PT-ECFCs, and acts as a critical determinant of the PT-ECFC angiogenic defect. These findings lay new grounds for understanding the increased cardiovascular risk in individuals born prematurely and open perspectives for therapeutic strategy. (Blood. 2014;123(13):2116-2126

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Section: Discussionsupporting

confidence: 87%

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Vassallo

Simoncini

Ligi

et al. 2014

Blood

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“…As a consequence, EPCs play a pivotal role in restoring the supply of oxygen and nutrients to infarcted myocardium [7], ischemic limbs [8], and growing tumors [9]. Their regenerative potential renders EPCs particularly amenable for cell-based therapy, as discussed in several recent reviews [1,5,[10][11][12]. However, because of their paucity in samples collected from peripheral blood (PB), which may be too low to exert beneficial effects, and their uncertain differentiation fate, which may be harmful for the recipient, unveiling the signal transduction pathway regulating EPC behavior is essential to improve the outcome of cell-based therapy [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…Their regenerative potential renders EPCs particularly amenable for cell-based therapy, as discussed in several recent reviews [1,5,[10][11][12]. However, because of their paucity in samples collected from peripheral blood (PB), which may be too low to exert beneficial effects, and their uncertain differentiation fate, which may be harmful for the recipient, unveiling the signal transduction pathway regulating EPC behavior is essential to improve the outcome of cell-based therapy [10,11]. As well as PB-derived EPCs (PB-EPCs), the therapeutic potential of umbilical cord blood-derived EPCs (UCB-EPCs) has been shown in a recent study, in which the authors demonstrated that transplantation of expanded UCB-EPCs favored neovascularization in a mouse ischemic hind-limb model [13].…”

Section: Introductionmentioning

confidence: 99%

“…The finding that SOCE governs EPC proliferation highlights a novel alternative target to enhance the regenerative outcome of cell-based therapy. This latter approach mainly relies on 2 critical parameters: (1) EPC homing to ischemic organs and (2) EPC incorporation into newly growing vessels, proliferation, and differentiation into mature ECs [10][11][12]. Therefore, once established the molecular machinery underlying SOCE in EPCs, transfecting autologous cells with genes encoding for the identified channels could be instrumental to augment EPC number and improve neovascularization.…”

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confidence: 99%

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Store-Operated Ca²⁺ Entry Is Expressed in Human Endothelial Progenitor Cells

Sanchez-Hernandez

Laforenza

Bonetti

et al. 2010

Stem Cells and Development

103

226

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Endothelial progenitor cells (EPCs) may be recruited from the bone marrow to sites of tissue regeneration to sustain neovascularization and reendothelialization after acute vascular injury. This feature makes them particularly suitable for cell-based therapy. In mature endothelium, store-operated Ca(2+) entry (SOCE) is activated following emptying of inositol-1,4,5-trisphosphate-sensitive stores, and controls a wide number of functions, including proliferation, nitric oxide synthesis, and vascular permeability. The present work aimed at investigating SOCE expression in EPCs harvested from both peripheral blood (PB-EPCs) and umbilical cord blood (UCB-EPCs) by employing both Ca(2+) imaging and molecular biology techniques. SOCE was induced upon either pharmacological (ie, cyclopiazonic acid) or physiological (ie, ATP) depletion of the intracellular Ca(2+) pool. Further, store-dependent Ca(2+) entry was inhibited by the SOCE inhibitor, N-(4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP-2). Real-time reverse transcription-polymerase chain reaction and western blot analyses showed that both PB-EPCs and UCB-EPCs express all the molecular candidates to mediate SOCE in differentiated cells, including TRPC1, TRPC4, Orai1, and Stim1. Moreover, pharmacological maneuvers demonstrated that, as well as in differentiated endothelial cells, the signal transduction pathway leading to depletion of the intracellular Ca(2+) pool impinged on the phospholipase C/inositol-1,4,5-trisphosphate pathway. Finally, blockage of SOCE with BTP-2 impaired PB-EPC proliferation. These findings provide the first evidence that EPCs express SOCE, which might thus be regarded as a novel target to enhance the regenerative outcome of cell-based therapy.

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“…A few studies have recently demonstrated that bone marrowderived progenitor cells significantly contribute to re-endothelialization after endothelial cell injury. 24,25 Utilizing anti-CD34 mAb targeting to CD34 antigens on the surface of EPCs has been recently reported for coronary stent (stainless steel) and graft material (ePTFE), which were very effective in in vivo pre-clinical and clinical studies. [26][27][28] In this study, a novel CD34 mAb-immobilized PU graft material was prepared using a unique method to achieve in vivo endothelialization.…”

Section: Introductionmentioning

confidence: 99%

CD34 monoclonal antibody-immobilized electrospun polyurethane for the endothelialization of vascular grafts

et al. 2010

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Targeting endothelial progenitor cells (EPC) for in vivo endothelialization is an emerging and promising approach for the development of cardiovascular medical devices. This study examined the efficacy of capturing CD34 positive EPC onto polyurethane (PU) immobilized with CD34 monoclonal antibodies (mAbs) (a biomecial polymer for cardiovascular devices). Electrospun PU matrices were fabricated and heparin was immobilized along with CD34 mAb. The modified PU surfaces at each step were characterized by contact angle measurements, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). XPS showed that each surface was modified, as expected in terms of the chemical composition. The amine-terminated poly(ethylene glycol)(PEG)-PU surface was considerably more hydrophilic than the PU surface. In addition, its surface roughness was similar to the PU surface, indicating that PEG was sufficiently and evenly grafted onto the PU surface. The CD34 mAb-immobilized PEG-PU surface was less hydrophilic than PEG-PU and extremely rough as compared to the other two surfaces. These results demonstrate that relatively large CD34 mAbs were immobilized on the PU surface. The surface density of the immobilized CD34 mAb, which was quantified using an enzymelinked immune-sorbent assay (ELISA), was increased to ~40 ng/cm 2 by varying the feed amount up to ~200 ng/ cm 2 and co-immobilizing with heparin. These results suggest that the co-immobilization with heparin can provide two benefits: inhibiting initial occlusion and improving the surface density of CD34 mAb. The in vitro cell study also demonstrated that the CD34 mAb-immobilized PU surface was favorable for cell attachment and proliferation. Therefore, in this study, a novel approach was developed to achieve endothelialization for cardiovascular applications by immobilizing CD34 onto PU, and the synergistic effects of co-immobilization with heparin on the bioactivity of the PU surfaces was demonstrated.

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Endothelial progenitor cells as therapeutic vectors in cardiovascular disorders: From experimental models to human trials

Cited by 44 publications

References 108 publications

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Store-Operated Ca²⁺ Entry Is Expressed in Human Endothelial Progenitor Cells

CD34 monoclonal antibody-immobilized electrospun polyurethane for the endothelialization of vascular grafts

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Endothelial progenitor cells as therapeutic vectors in cardiovascular disorders: From experimental models to human trials

Cited by 44 publications

References 108 publications

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Accelerated senescence of cord blood endothelial progenitor cells in premature neonates is driven by SIRT1 decreased expression

Store-Operated Ca2+ Entry Is Expressed in Human Endothelial Progenitor Cells

CD34 monoclonal antibody-immobilized electrospun polyurethane for the endothelialization of vascular grafts

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Product

Resources

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Store-Operated Ca²⁺ Entry Is Expressed in Human Endothelial Progenitor Cells